192 J Nippon Med Sch 2019; 86 (4)

―Review―

Fetal and Neonatal Circulatory Disorders

in Twin to Twin Transfusion Syndrome (The Secondary Publication)

Hitoshi Yoda

Department of Neonatology, Toho University, Faculty of Medicine, Tokyo, Japan

Twin to twin transfusion syndrome (TTTS) is a major complication of monochorionic diamniotic (MD)

twins, and its onset is known to be associated with placental vascular anastomoses and blood flow im-

balance. In a typical case of TTTS, the recipient develops polyhydramnios, weight gain, cardiomegaly

and hydrops fetalis in the uterus. In contrast, the donor develops oligohydramnios and intrauterine

growth restriction. Recently, the significance of the renin-angiotensin-aldosterone system (RAAS) that

transfers from the donor to the recipient has attracted interest in the fetal circulation of TTTS. The do-

nor has decreased renal blood flow due to decreased circulating blood volume. For this reason, the se-

cretion of RAAS hormones is augmented in the fetal kidneys of the donor. In TTTS, these RAAS hor-

mones from the donor transfer to the recipient through the anastomosed vessels. In addition to excess

preload, the recipient heart is exposed to excess afterload due to systemic vasoconstriction through

RAAS hormones. Commonly occurring complications in the recipient include myocardial hypertrophy,

atrioventricular valve regurgitation, and pulmonary valve stenosis or pulmonary atresia. Fetoscopic la-

ser photocoagulation (FLP) has been introduced recently because neither mortality nor neurological

morbidity have been satisfactorily improved with conventional treatment. FLP is a curative method that

may improve the prognosis of TTTS. In Japan, this procedure has been performed frequently, and posi-

tive neurological outcomes have been achieved. (J Nippon Med Sch 2019; 86: 192―200)

Key words: twin to twin transfusion syndrome (TTTS), recipient, cardiomyopathy, cardiac anomaly, fe-

toscopic laser photocoagulation (FLP)

Pathology and Definition of TTTS

Twin to twin transfusion syndrome (TTTS) is a complica-

tion that is observed in about 10 to 30% of monochori-

onic diamniotic (MD) twins1―3, and its onset is known to

be associated with placental vascular anastomoses and

blood flow imbalance. Twins in TTTS are commonly re-

ferred to as the recipient or the donor. In a typical case of

TTTS, the recipient develops polyhydramnios, weight

gain, cardiomegaly, and effusion into body cavity (hy-

drops fetalis) during the fetal stage and shows signs such

as plethora, hypertension, polyuria, cardiomegaly, and

hydrops fetalis postnatally. In contrast, the donor devel-

ops oligohydramnios and fetal growth restriction during

the fetal stage and shows signs such as anemia, oliguria,

renal failure, and oligohydramnios sequence postnatally.

There is, however, a broad spectrum of signs and symp-

toms in TTTS. Classically, TTTS was evaluated based on

observing the differences in birth weight or in hemoglo-

bin level in the neonates4,5. However, with the advances

and widespread use of ultrasound examinations, TTTS is

currently diagnosed by assessing the presence of twin of

oligohydramnios-polyhydramnios sequence (TOPS), a

condition in which monochorionic twins present an ex-

cess and deficiency of amniotic fluid during the fetal

stage6. Consequently, it has become standard practice to

define TTTS as MD twins presenting abnormally large

and small volumes of amniotic fluid with maximum ver-

tical pockets of >8 cm and <2 cm, respectively. The stag-

ing system proposed by Quintero et al.7 classifies the pro-

gression of TTTS as follows: 1) presence of amniotic fluid

Correspondence to Hitoshi Yoda, MD, Department of Neonatology, Toho University, Faculty of Medicine, 6―11―1 Omori-nishi,

Ota-ku, Tokyo 143―8541, Japan

E-mail: yoda@med.toho-u.ac.jp

https://doi.org/10.1272/jnms.JNMS.2019_86-301

Journal Website (https://www.nms.ac.jp/sh/jnms/)

Fetal and Neonatal Circulatory Disorders in Twin to Twin Transfusion Syndrome (The Secondary Publication)

J Nippon Med Sch 2019; 86 (4) 193

Table　1　Staging of TTTS based on sonographic and doppler findings5. Quintero RA

Stage Poly/oligohydramnios* Absent bladder in donor CADs† Hydrops Demise

I + – – – –

II + + – – –

III + + + – –

IV + + + + –

V + + + + +

*Polyhydramnios, MVP of >8 cm; oligohydramnios, MVP of <2 cm.

†CADs, defined as the presence of at least one of the following: (1) UA AEDV/REDV, (2) RFDV, or

(3) pulsatile umbilical venous flow (PUVF).

excess and deficiency represented by maximum vertical

pockets of >8 cm and <2 cm, respectively; 2) undetectable

urinary bladder in the donor twin; 3) abnormal fetal

blood flow (absence or reverse diastolic flow of the um-

bilical artery, pulsation waving flow of the umbilical

vein, reverse diastolic flow of the ductus venosus); 4)

presence of hydrops fetalis; and 5) fetal death of one of

the twins (Table 1). This staging is also used to deter-

mine when to start treatment using the recently-

developed selective fetoscopic laser photocoagulation

(FLP) to ablate placental anastomoses in the fetus and to

assess the effects of such treatment8.

Hemodynamics and Endocrine Environment in TTTS

Recently, the significance of the renin-angiotensin-

aldosterone system (RAAS) that transfers from the donor

to the recipient has attracted interest in the fetal circula-

tion of TTTS9. As described above, the recipient and do-

nor share one placenta in TTTS, and there is a chronic

transfer of blood from the donor to the recipient via vas-

cular anastomoses. This results in a volume overload in

the recipient and the opposite in the donor. Increased cir-

culating blood volume in the recipient leads to excess

preload. For this reason, there is augmented secretion of

natriuretic peptides such as atrial natriuretic peptide

(ANP) and B-type natriuretic peptide (BNP) and of endo-

thelin 1, inducing an increase in urine production10. On

the other hand, the donor has decreased renal blood flow

due to decreased circulating blood volume, causing a de-

crease in fetal urine. For this reason, the secretion of

renin/angiotensin/aldosterone system, known as RAAS

hormones, is augmented in the fetal kidneys of the do-

nor. In TTTS, these RAAS hormones from the donor

transfer to the recipient through the anastomosed vessels.

This raises the levels of RAAS hormones in the recipient

even though the recipient has an elevated circulating

blood volume, and this consequently triggers a “para-

doxical RAAS activation,” also known as the “two-

kidney one-clip” model11. Thus, in addition to excess pre-

load, the recipient heart is exposed to excess afterload

due to systemic vasoconstriction through RAAS hor-

mones and endothelin 1, inducing conditions such as

vascular obstructive lesions, hypertension, and cardio-

myopathy. Additionally, due to the effects of RAAS hor-

mones in inducing myocardial fibrosis and thickening,

the recipient may also develop a condition akin to fetal

cardiomyopathy12. Such hemodynamics and the endo-

crine environment are considered to be the origin of the

various circulatory disorders in both donor and recipi-

ent13 (Fig. 1).

Cardiovascular Complications Observed in TTTS

The aforementioned hemodynamics reflect the various

cardiac complications that arise in TTTS. In particular,

the distinctive cardiac complications in the recipient are

of particular interest. Cardiovascular conditions that stem

from a combination of volume overload from increased

circulating blood volume and pressure overload from hy-

pertension or outflow tract impairment are the most

common complications in the recipient. Highly-frequent

complications include myocardial hypertrophy, atrioven-

tricular valve regurgitation, and persistent pulmonary

hypertension of the newborn, and they have been consid-

ered not to be associated with a structural anomaly14.

However, there are cases in which the condition has pro-

gressed to pulmonary valve stenosis or pulmonary

atresia (including functional pulmonary atresia), requir-

ing surgical or catheter treatment in severe cases, and

this, together with its etiology, has consequently attracted

interest15. Although cardiac complications are not as com-

mon in donors as in recipients, complications such as

aortic coarctation are rather distinctive in donors based

on the flow theory16, where there is poor aorta growth,

reflecting the hemodynamics of a decreased systemic

blood flow17.

It is traditionally known that twins have a greater rate

H. Yoda

194 J Nippon Med Sch 2019; 86 (4)

Fig.　1　Cardiac complications of the recipient:

Focusing on the intrauterine hemodynamics of the twin to twin transfusion syn-

drome. (RAS: renin-angiotensin system, AT II: angiotensin II, NF: natriuretic fac-

tor)

(Reprinted by courtesy of S. Karger AG, Basel from “Machiew-Caputo D, et al.:

Pathogenesis of twin-twin transfusion syndrome: the renin-angiotensin system hy-

pothesis. Fatal Diagn Ther 16; 241-244, 2001.”)

of developing congenital heart diseases compared to sin-

gletons; according to a systematic review of 45 articles by

Bahtiyar et al.18, the incidence was 6- to 10-fold greater in

MD twins and 15- to 23-fold greater in MD twins with

TTTS compared to singletons. In terms of the types of

diseases, aside from ventricular septal defect that is gen-

erally observed with high frequency, right heart disorders

(such as pulmonary valve stenosis and pulmonary

atresia) in the recipient are notable. Although the causes

of such highly-frequent cardiac complications can only be

guessed, it is necessary to consider genetic factors in

which a placental anomaly of twin gestation affects the

fetus. In particular, the involvement of the angiogenesis

factor such as vascular endothelial growth facter(VEGF),

which is activated in an ischemic condition, has attracted

attention19, indicating that the hemodynamic state itself

plays a key role in the onset of heart diseases in TTTS.

Cardiovascular Complications Observed

in the Recipient

1. Myocardial Hypertrophy (Hypertrophic Cardio-

myopathy)

In our previous survey, myocardial hypertrophy was

observed on examination in most TTTS recipients during

the fetal and postnatal stages20. Others have also reported

that the incidence of myocardial hypertrophy during the

fetal age is high, at about 50%21. Recently, a new TTTS fe-

tal evaluation system of cardiovascular score (CV score)

was proposed, where indices such as ventricular hy-

pertrophy, cardiac dilatation, ventricular dysfunction,

atrioventricular valve regurgitation, atrioventricular dia-

stolic filling, pulmonary artery size, right ventricle out-

flow obstruction, pulmonary valve regurgitation, ductus

venous reverse flow, and umbilical venous pulsation

waveform in the recipient are measured using echocar-

diography in addition to umbilical artery finding in the

donor22 (Table 2). Each parameter was given a numeric

value based on the degree of severity of the finding with

a total maximum of 20 points. CV score was graded to

four degree for severity of cardiovascular abnormality.

Unlike Quintero’s staging, which is largely based on do-

nor characteristics such as abnormal blood flow, this

method evaluates the recipient’s cardiac complications,

aiming to classify the TTTS severity with greater accu-

racy. In heart failure pathology that progresses from the

fetal stage as described, ventricular dilatation caused by

myocardial hypertrophy has been emphasized, and this

is measured by the myocardial performance index (MPI,

Tei index)23. Despite their poor postnatal condition, many

of these recipients with myocardial hypertrophy present

with hypertension at birth. Furthermore, most recipients

show cardiac dilatation with a cardiothoracic ratio (CTR)

�60% on chest X-ray. Echocardiography shows myocar-

dial hypertrophy that exceeds the normal myocardial

Fetal and Neonatal Circulatory Disorders in Twin to Twin Transfusion Syndrome (The Secondary Publication)

J Nippon Med Sch 2019; 86 (4) 195

Table　2　Cardiovascular score22 Rychik J

Variable Parameter Finding Numeric score

Donor Umbilical artery Normal 0

Decreased diastolic flow 1

absent/reversed diastolic flow 2

Recipient Ventricular hypertrophy None 0

Present 1

Cardiac dilatation None 0

Mild 1

>mild 2

Ventricular dysfunction None 0

Mild 1

>mild 2

Tricuspid valve regurgitation None 0

Mild 1

>mild 2

Mitral valve regurgitation None 0

Mild 1

>mild 2

Tricuspid valve inflow Double-peak 0

Single-peak 1

Mitral valve inflow Double-peak 0

Single-peak 1

Ductus venosus All antegrade 0

Absent diastolic flow 1

Reverse diastolic flow 2

Umbilical vein No pulsation 0

Pulsation 1

Right-sided outflow tract Pulmonary artery > Aorta 0

Pulmonary artery = Aorta 1

Pulmonary artery < Aorta 2

Right ventricle outflow obstruction 3

Pulmonary regurgitation None 0

Present 1

wall thickness (adjusted to body weight) by +2SD and

marked tricuspid regurgitation (Fig. 2). Although the left

ventricular ejection fraction is typically within the normal

range, some show early stages of decreased contractile

force, and myocardial hypertrophy emerges in these

cases once the contractile force is improved. Myocardial

hypertrophy is known to normalize in 10 days to 2

months, indicating its characteristic reversible nature14.

Autopsy examination has shown a narrowing of the ven-

tricular lumen due to thickening of the ventricular sep-

tum and posterior wall, and histopathological examina-

tion has shown distinctive myocardial hypertrophy, and

in part endocardial fibroelastosis3,24. (Fig. 3)

2. Pulmonary Artery Stenosis and Atresia (Fig. 4)

As cardiac complications in the recipient, severe pul-

monary artery stenosis and atresia do not occur as fre-

quently as the aforementioned myocardial hypertrophy

or hydrops fetalis. However, it is postulated that right

ventricular outflow tract obstruction and pulmonary

valve degeneration and stenosis may occur concomi-

tantly with myocardial hypertrophy because they occur

specifically in the recipient. Their severity varies, and

some serious cases require pulmonary valvotomy using a

balloon25,26. The authors have also treated two cases

where balloon pulmonary valvotomy was required. It has

been hypothesized that15 pulmonary artery stenosis de-

velops in the TTTS recipient through an increase in sys-

temic vascular resistance due to augmented vascular re-

sistance in the umbilical artery, increasing the ventricular

pressure, especially the right ventricular pressure. This

causes right ventricular hypertrophy and tricuspid regur-

gitation, hindering forward ejection from the right ventri-

cle, thereby inducing pulmonary artery stenosis and

atresia. In the authors’ experience, it is observed in 5% of

recipients, similar to the incidence reported by others27,28.

H. Yoda

196 J Nippon Med Sch 2019; 86 (4)

Fig.　2　Neonatal echocardiography of the recipient:

(Left) Hypertrophic cardiomyopathy with prominent tricuspid and mitral regurgitation from

four chamber view. (Right) Hypertrophic cardiomyopathy from short axis view

Fig.　3　The myocardial pathology of the recipient.:

(Left) The loupe image shows both of the left and the right heart chambers occupied with the

myocardial hypertrophy. (Right) With the HE stain, the myocardial cells are lucid, different

from the disarray formation observed with the adult hypertrophic cardiomyopathy.

10mm

Fig.　4　Severe pulmonary artery stenosis in the recipient:

(Left) Fast pulmonary artery flow velocity (estimatedΔP=102 mmHg). (Right) Tricuspid valve regurgita-

tion Pressure gradient ΔP=95 mmHg .

Fetal and Neonatal Circulatory Disorders in Twin to Twin Transfusion Syndrome (The Secondary Publication)

J Nippon Med Sch 2019; 86 (4) 197

Fig.　5　A fetal echocardiography of a recipient:

(Left) Distinctive myocardinal hypertrophy is observed from the fetal stage, with atrioventricular

regurgitation in the four chamber view. (Right) Tricuspid regurgitation flow measures 4.2 m/s,

and with the conventional Bernoulli’s formula (pressure gradient = 4× velosity2), the pressure

gradient between the right ventricle (RV) and the right atrium (RA) are calculated to be 70 mmHg,

which means considerably high RV pressure as a fetus. It is recognized to be the cause of the re-

cipient’s fetal hydrops.

TR(v=4.2m/s)PG=70mmHgRV

LV

Fig.　6　A fetal sonography of a representative critical twin to twin transfusion syndrome:

The polyhydroamnios of a recipient (the larger twin) and the oligohydroamnios of a donor (the

smaller twin). A donor is stuck on the uterine wall and the recipient has fetal hydrops and ascites.

Larger twin

Smaller twin

3. Atrial Septal Defect

The postulated mechanism for the onset of this condi-

tion is as follows: first, there is a synergistic effect of

high-output heart failure and right ventricular outflow

tract obstructive lesions in the recipient, followed by an

increase in shunt via the foramen ovale, thereby having a

destructive effect on the atrial septum. However, it is ac-

tually unclear whether the atrial septal defect is due to a

septal tissue defect or enlargement associated with in-

creased shunt flow18.

4. Hydrops Fetalis

Hydrops fetalis is observed very frequently in the re-

cipient from the fetal stage. Fetal hypertension has been

highlighted as its mechanism, and the baseline disease

state is considered to involve a secondary hypertensive

myocardial hypertrophy and hypertensive polyuria

(polyhydramnios). In cases with atrioventricular valve re-

gurgitation, fetal heart failure occurs, progressing to hy-

drops fetalis (Fig. 5)20. The signs of fetal heart failure pro-

gress from subcutaneous edema, ascites, and pericardial

effusion to pleural effusion, leading to severe hydrops fe-

talis(Fig. 6). This condition poses a threat of intrauterine

fetal death and requires neonatal treatment after delivery,

although complications caused by prematurity can be le-

thal in markedly preterm births, creating extreme diffi-

culties in treatment.

5. Rare Complications

・Left ventricular outflow tract obstruction (Fig. 7)

In marked cases of hypertrophic cardiomyopathy, left

ventricular outflow tract obstruction may appear together

with right ventricular outflow tract obstruction. The

hemodynamics in this situation are similar to those in

H. Yoda

198 J Nippon Med Sch 2019; 86 (4)

Fig.　7　Hypertrophic obstructive cardiomyopathy with left ventricular outflow tract obstruction

in the recipient:

(Left) four chamber view. (Right) LV outflow view. In this case, the stenosis improves

with the use of propranolol

Fig.　8　Ventricular aneurysm and pericardial effusion:

(Left) A thin-walled ventricular aneurysm (arrow) that communicated with the right ventricular

apex was also present. (Right) Autopsy findings showed hemorrhagic pericardial effusion and a

fully-thrombosed ventricular aneurysm (arrow)

hypertrophic obstructive cardiomyopathy. In the authors’

experience, with pulmonary valve stenosis, a further ex-

acerbation in myocardial hypertrophy that is characteris-

tic of TTTS recipients is observed because volume over-

load decreases after patent ductus arteriosus ligation,

leading to left ventricular outflow tract obstruction. In

this case, the stenosis improves with the use of propra-

nolol29.

・Ventricular aneurysm and pericardial effusion (Fig.

8)

In the authors’ experience, bilateral lung retractions

were observed in a recipient due to a large volume of

pericardial effusion, and a thin-walled ventricular aneu-

rysm that communicated with the right ventricular apex

was also present. Autopsy findings showed hemorrhagic

pericardial effusion and a fully-thrombosed ventricular

aneurysm. The aneurysm histologically showed severe

myocardial damage and marked fibrosis29. Although ad-

vanced myocardial ischemia has been postulated to be its

trigger, a clear cause has yet to be established.

Cardiovascular Complications of Fetoscopic Laser

Photocoagulation of Placental Anastomoses (Fig. 9)

Although selective FLP to treat placental anastomoses

can be performed only at a limited number of institu-

tions at the present time, it is a curative method by

Fetal and Neonatal Circulatory Disorders in Twin to Twin Transfusion Syndrome (The Secondary Publication)

J Nippon Med Sch 2019; 86 (4) 199

Fig.　9　Fetoscopic laser photocoagulation (FLP).:

The venous-arterial, venous-venous, and arterial-arterial vascular anastmoses are coagu-

lated with the laser under the fetoscopy. It can be performed only in the certain medical

centers, however, is a cure, treating the cause of the TTTS.

recipient

donor

fetoscope

US

membrane

which the cause of TTTS is eliminated. It is also expected

to be a therapeutic method that improves the prognosis

of TTTS. In Japan, the procedure has been performed in-

creasingly more frequently, and positive neurological out-

comes have been achieved30,31. Recent reports have indi-

cated that the aforementioned cardiovascular disorders

can remain even after FLP treatment, and there are fre-

quently observed right side cardiac anomalies in the re-

cipient, appeared as pulmonary artery stenosis and func-

tional atresia7,32,33. The authors have also experienced cases

where functional pulmonary valve atresia developed af-

ter birth, similar to reports that described a right-side cir-

cular shunt where the ductus arteriosus flow also had a

left-to-right shunt due to the presence of pulmonary ar-

tery regurgitation and tricuspid regurgitation from the fe-

tal stage34,35. As described, cardiovascular complications

can remain even after curative therapy for TTTS. These

complications are similar to those observed in TTTS

without fetal therapy, and the occurrence of such compli-

cations, especially right ventricular outflow tract obstruc-

tive lesions, should not be overlooked. To distinguish re-

versible lesions from those non-reversible is necessary,

and establishment of registration system by accumulating

detailed data through careful clinical practice would be

the future goal to treat successfully this pathophysiology

in Japan.

Editorial Comment: This article is based on a study first

reported in Japanese in the Journal of the Medical Society

of Toho University 2013; 60; 24-31. Because we think the

content will be of great interest to J Nippon Med Sch

readers, the Editorial Board requested that the authors

submit it as a special review article for publication in our

journal. (The content of the original Japanese article has

been added to in this English version.)

Conflict of Interest: The Authors declare no conflict of inter-

est.

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(Received,

(Accepted,

May

February

30, 2017)

14, 2019)